Luminescent Oxygen Nanosensors for Tumor Hypoxia Imaging

描述(申请人提供)：氧合作用在健康和医学中起着至关重要的作用。细胞、组织和生物体的缺陷或过量与疾病、损伤、愈合不良，甚至死亡有关。例如，缺氧与癌症的进展、转移和对治疗的抵抗有关。缺氧诱导因子1(HIF-1)在低氧环境中的表达可以加速血管生成，促进肿瘤存活，当没有活性氧时，放疗和药物治疗可能不那么有效，当缺乏活性氧来增强肿瘤损伤时，或者当缺氧导致肿瘤微环境改变时，否则会影响药物的输送和作用。尽管氧分压(PO2)对生物医学很重要，但它的评估通常仅限于氧耗率(OCR)测量、侵入性探头或昂贵的成像手段。通常，方法只提供整个细胞群体的平均值，或者被限制在空间或时间上的单点测量。该项目的长期目标是开发一套通用的PO2成像技术材料和平台，以加强临床前研究，并在许多医学背景下帮助诊断、治疗和手术。在概念验证研究的成功和我们团队在材料合成、成像和癌症生物学方面的优势的基础上，这项应用的目标是开发双发射二氟硼？-二酮-聚乳酸(BF2bdkPLA)染料聚合物纳米颗粒(BNPS)，并结合成像方法在体外和体内小鼠模型中进行乳腺癌的发光检测和比率O2传感。这一目标将通过追求以下具体目标来实现：1)将对BNP染料进行化学修饰，以实现广泛的发射颜色调节和氧敏感性调节；将开发成像方法，用于体外比率O2传感(即荧光(F)和磷光(P)检测)。2)BNP聚合物将适用于被动和主动靶向PO2监测，具有更好的空间特异性；靶向BNPS将在体外和体内进行研究。3)BNP乏氧显像剂将在小鼠乳房窗口模型中测试其检测肿瘤、监测肿瘤进展以及随时间推移的放射和化疗反应的能力。拟议的成本效益技术是创新的，因为与现有方法相比，它能够通过模块化、可调、可综合访问的材料平台实现动态缺氧成像，并具有更高的空间和时间组合分辨率。预期的结果是一种多功能的氧纳米传感器技术，与常见的光学成像方式相结合，以量化细胞、组织和体内的pO2。BNPS具有更强的特异性、组织穿透性 光，并将产生多路复用能力。这项工作将对癌症CAR产生积极的影响，因为它将更好地阐明缺氧、癌症进展和治疗方案之间的关系。最终，BNPS将通过帮助绘制氧合和生物功能之间的关系来阐明许多医学挑战。这一点已经实现了。

DESCRIPTION (provided by applicant): Oxygenation plays a critical role in health and medicine. Deficits or excesses in cells, tissues and organisms are associated with disease, damage, poor healing, and even death. For example, hypoxia is implicated in cancer progression, metastasis, and resistance to therapies. Hypoxia inducible factor 1 (HIF-1) expression in low oxygen environments accelerates angiogenesis and promotes tumor survival, and radiation and drug treatments can be less effective when reactive oxygen is not present to enhance the tumor damage or when hypoxia-induced changes in the tumor microenvironment otherwise affect drug delivery and action. Despite the importance of oxygen partial pressure (pO2) to biomedicine, its assessment is often limited to oxygen consumption rate (OCR) measurements, invasive probes, or expensive imaging modalities. Often methods provide only average values for whole populations of cells, or are restricted to single point measurements in space or time. The long-term goal of this project is to develop a versatile material set and platform of pO2 imaging technologies that can enhance preclinical studies and aid in diagnosis, treatment and surgery in many medical contexts. Building upon success in proof of concept studies and the strengths of our team in materials synthesis, imaging, and cancer biology, the objective of this application is to develop dualemissive difluoroboron ?-diketonate-poly(lactic acid) (BF2bdkPLA) dye-polymer nanoparticles (BNPs) in conjunction with imaging methodologies for luminescence detection and ratiometric O2 sensing in breast cancer in vitro and in vivo mouse models. This objective will be accomplished by pursuing the following specific aims: 1) BNP dyes will be chemically modified for broad range emission color tuning and oxygen sensitivity modulation; imaging methods will be developed for their use in in vitro ratiometric O2 sensing (i.e. both fluorescence (F) and phosphorescence (P) detection). 2) BNP polymers will be adapted for passive and active targeting for pO2 monitoring with improved spatial specificity; targeted BNPs will be investigated in vitro and in vivo. 3) BNP hypoxia imaging agents will be tested for their ability to detect tumors, and to monitor tumor progression and radiation and chemotherapy response over time in a mouse mammary window model. The proposed cost- effective technology is innovative because it enables dynamic hypoxia imaging with improved combined spatial and temporal resolution compared to existing approaches with a modular, tunable, synthetically accessible materials platform. The expected outcome is a versatile oxygen nanosensor technology in conjunction with common optical imaging modalities to quantify pO2 in cells, tissues and in vivo. BNPs with greater specificity, tissue penetration of light, and multiplexing capability will result. This work will have a positive impact on cancer car because it will better illuminate the relationships between hypoxia, cancer progression, and treatment protocols. Ultimately, BNPs will shed light on many medical challenges by helping to map relationships between oxygenation and biological function. This is already being realized.